Intermittent Fasting‐Induced Orm2 Promotes Adipose Browning via the GP130/IL23R‐p38 Cascade

Intermittent fasting (IF) plays a critical role in mitigating obesity, yet the precise biological mechanisms require further elucidation. Here Orosomucoid 2 (Orm2) is identified as an IF‐induced hepatokine that stimulates adipose browning. IF induced Orm2 expression and secretion from the liver through peroxisome proliferator‐activated receptor alpha (PPAR α) . In adipose tissue, Orm2 bound to glycoprotein 130/interleukin 23 receptor (GP130/IL23R) and promoted adipose browning through the activation of p38 mitogen‐activated protein kinases (p38‐MAPK). In obese mice, Orm2 led to a significant induction of adipose tissue browning and subsequent weight loss, an effect that is not replicated by a mutant variant of Orm2 deficient in GP130/IL23R binding capability. Crucially, genetic association studies in humans identified an obesity‐associated Orm2 variant (D178E), which shows decreased GP130/IL23R binding and impaired browning capacity in mice. Overall, the research identifies Orm2 as a promising therapeutic target for obesity, mediating adipose browning through the GP130/IL23R‐p38 signalling pathway.